Radiation therapy (RT) remains the most important non-surgical treatment in the management of solid malignancies with around 50-60% of all cancer patients receiving this treatment. The inclusion of RT in treatment regimens reduces disease recurrence and improves overall survival in the majority of common cancers (1-3). Although effective, many patients suffer from local recurrence and metastatic disease.
In addition to the direct cytoreductive effect of RT, emerging evidence suggests that the generation of anti-tumor immune responses may play an important role in the effectiveness of this treatment (4, 5). RT can lead to expression of ecto-calreticulin on tumor cells as well as the release of several damage-associated molecular patterns (DAMPs) including High Mobility Group Box 1 (HMGB1) and ATP which can lead to recruitment and activation of antigen presenting cells (APCs) and priming of tumor antigen-specific T cell responses (6-10). Despite this immune-escape frequently occurs, with tumor recurrence remaining the leading cause of mortality in patients receiving RT (11). The identification and inhibition of key drivers of immunosuppression may augment anti-tumor immune responses with the potential to improve patient outcome.
New insights into treatment failure and more effective RT combination approaches are therefore urgently required.
The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is involved in the maintenance of peripheral tolerance and the modulation of acute inflammatory responses through inhibition of T cell function and through apoptosis of activated T cells (12, 13). In addition to binding PD-1, PD-L1 can also suppress T cell function through interaction with CD80 (14). Expression of PD-L1 is inducible and thought to respond to local inflammatory milieu, particularly type I and II interferon (IFN) (12, 15, 16). Although barely detectable in most normal tissues, expression of PD-L1 has been described in multiple malignancies (reviewed in (17)). Importantly, recent clinical studies with either PD-1 or PD-L1 targeting monoclonal antibodies (mAb) have demonstrated encouraging responses in patients with advanced disease (18-21).
A dosing strategy for combining radiation therapy and a PD-1 and/or PD-L1 antagonist is desired to create maximal benefit for patients suffering from cancer.